Ruthenium-Catalyzed Direct Dehydrogenative Cross-Coupling of Allyl Alcohols and Acrylates: Application to Total Synthesis of Hydroxy β-Sanshool, ZP-Amide I, and Chondrillin

Article abstract of DOI:10.1021/acs.orglett.0c00200

Ru-catalyzed oxidative coupling of allyl alcohols and activated olefins has been developed by C(allyl)-H activation of allyl alcohols providing efficient and direct access to synthetically useful α,β-unsaturated enone intermediates. Synthetic utility of this method was demonstrated by its application to synthesis of bioactive natural products such as Hydroxy-β-sanshool, ZP-amide I, Chondrillin, Plakorin, and (+)-cis-Solamin A.

Full text of DOI:10.1021/acs.orglett.0c00200

pubs.acs.org/OrgLett
Letter
Ruthenium-Catalyzed Direct Dehydrogenative Cross-Coupling of
Allyl Alcohols and Acrylates: Application to Total Synthesis of
Hydroxy β‑Sanshool, ZP-Amide I, and Chondrillin
Dattatraya H. Dethe* and Nagabhushana C B
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ABSTRACT: Ru-catalyzed oxidative coupling of allyl alcohols and
activated olefins has been developed by C(allyl)−H activation of allyl
alcohols providing efficient and direct access to synthetically useful α,β-
unsaturated enone intermediates. Synthetic utility of this method was
demonstrated by its application to synthesis of bioactive natural products
such as Hydroxy-β-sanshool, ZP-amide I, Chondrillin, Plakorin, and
(+)-cis-Solamin A.
Scheme 1
arbon−carbon bond forming reactions are the backbone
Cof organic synthesis. These reactions give access to an
important class of compounds such as alkanes, alkenes, and
alkynes. Thus, development of novel approaches for the
carbon−carbon bond formation is a continuous process in
organic synthesis. So, several synthetic approaches for
accessing alkenes have been reported such as Wittig
reaction,1−6 olefin metathesis,7−13 metal-catalyzed cross-
coupling reactions, and many more.14−19 However, many of
these methods suffer from poor atom economy and use of toxic
reagents. Thus, it is highly desirable to develop cheap,
selective, and highly atom-economical reactions to access
alkenes. Therefore, to overcome aforementioned limitations
for synthesis of alkenes, recently developed approaches rely on
transition-metal-catalyzed alkenyl C−H bond coupling reac-
tions, as these reactions are performed in a catalytic, atom- and
step-economic manner.20−31 Most importantly, the Loh group
reported an elegant method for the stereoselective synthesis of
muconate derivatives via ruthenium-catalyzed sp2 C−H
activation (Scheme 1a).23 White and co-workers developed a
Pd(II)/sulfoxide-catalyzed oxidative Heck vinylation reaction
strategy for carbon−carbon bond formation.35−38 Surprisingly,
ruthenium-catalyzed alkene−alkene coupling reactions are
underdeveloped. Trost and co-workers disclosed an inventive
method for highly chemoselective redox isomerization of allyl
alcohols using a ruthenium catalyst without affecting the
primary and secondary alcohols and isolated double bonds.39,40
Encouraged by the potentiality of ruthenium for such
isomerization of olefins in allyl alcohols, we sought to develop
a new method that can promote isomerization of olefin in allyl
alcohols as well as in situ formed enone can be oxidatively
coupled to an another activated olefin leading to a new
approach for the carbon−carbon bond forming process
for the synthesis of complex dienes and polyenes.32
A
palladium-catalyzed stereoselective alkenyl sp2 C−H bond
functionalization reaction was developed by Loh and co-
workers (Scheme 1b).33 In the past decade, several approaches
where a ruthenium(II)-catalyzed directing group facilitated C−
H bond activation/functionalization of aromatic compounds
have been reported;34 however, C−H bond activation/
functionalization of an alkene/alkane are less explored. In the
past three decades, Trost et al. have done pioneering work in
this field and extensively studied the ruthenium-catalyzed
alkynes−alkenes coupling reaction which is an atom-economic
Received: January 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00200
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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(Scheme 1c). In this context, herein, we report the highly
atom-/step-economical ruthenium-catalyzed sp2 C−H activa-
tion of allyl alcohols followed by a cross-coupling reaction with
activated olefins (Scheme 2).
lowering of the temperature led to noteworthy attenuation of
the reaction rate and yield.
With the optimized conditions in hand, we began to explore
the scope of the reaction. As shown in Table 2, a variety of
a
Table 2. Scope of Acrylates
Scheme 2. This Method
In this direction, we initiated our studies by choosing the
C−H activation reaction between substituted ally alcohol (1a)
and cyclohexyl acrylate (2a) as the model reaction (Table 1).
First, we investigated a variety of transition metal catalysts in
the presence of additive AgSbF6, Cu(OAc)2 in 1,2-dichloro-
ethane (DCE) at 60 °C (entries 1−4) for 16 h. The results
indicated that the reaction did not take place when
[Cp*RhCl2]2 (C1), Cp*Co(CO)I2 (C2), or [Cp Ru-
(CH3CN)3]PF6 (C3) were used as catalysts. In contrast, the
reaction afforded product 3a and 3a′ in 45% yield with good
regio- (80/20) and stereoselectivity when [RuCl2(p-cymene)]2
(C4) was employed as the catalyst. Subsequently, several
solvents were screened (entries 5−8). To our delight, the
catalytic system afforded the desired product 3a/3a′ with
excellent improvement in the regioselectivity (96/4) in good
yield (82%) when the reaction was conducted at 80 °C (entry
9). It was found that no reaction occurred in the absence of
Cu(OAc)2·H2O, and also replacement of Cu(OAc)2·H2O with
AgOAc and KOAc generated a trace amount of product 3a. It
confirms that the catalytic cycle involves a redox pathway. The
catalytic reaction was screened with various additive sources
such as Ag2CO3, AgOAc, and NH4PF6 (entrries 13−15).
These additives did not provide any satisfactory result; rather, a
very sluggish reaction rate or decomposition of starting
materials was observed in each case. It was found that the
reaction conditions for entry 9 to be the best, since further
a
Reaction conditions: 1 (0.20 mmol), 2 (0.22 mmol), [Ru(p-
cymene)Cl2]2 (5 mol %), additive (15 mol %) and oxidant (2 equiv)
at 80 °C in a 1,2-dichloroethane (3.0 mL) for 16 h. Isolated yields are
of product 3/3′. 1.5 equiv., of allyl alcohol 2c was used.
a
Table 1. Optimization of Reaction Conditions
f
entry
1
2
catalyst 5 (mol %)
additive 15 (mol %)
oxidant 2 (equiv)
solvent
yield (%)
3a/3a′ (%)
−
80/20
−
−
75/25
0
88/12
−
96/4
0
−
−
−
−
−
C1
C4
C2
C3
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
AgSbF6
AgSbF6
AgSbF6
−
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
−
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)22
−
KOAc
NaOAc
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
DCE
DCE
DCE
DCE
DCM
THF
dioxane
TFE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
0
45%
0
b
3
4
5
0
c
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
Ag2CO3
AgOAc
NH4PF6
10/25
0
18
trace
82
0
trace
trace
0
0
0
6
7
8
d
9
e
10
11
12
13
14
15
a
Reaction conditions: 1a (0.2 mmol), 2a (0.22 mmol), [Ru(p-cymene)Cl2]2 (5 mol %), additive (15 mol %), and oxidant (2 equiv) in a specific
b
c
d
solvent (3.0 mL) for 16 h. Reaction conducted at 60 °C for 10 h. Reaction conducted using DCM at 60/80 °C. Reaction conducted at 80 °C for
16 h. The reaction was performed without Cu(OAc)2·H2O. Isolated yields are of product 3a/3a′ w.r.t. acrylate 1a. TFE = Trifluoroethanol.
e
f
B
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pubs.acs.org/OrgLett
Letter
a
acrylates and allyl alcohols bearing different functionality
reacted well, providing the corresponding coupling products in
moderate to good yields with excellent stereoselectivity. For
example, acrylates with distinct alkyl substituents such as
cyclohexyl, methyl, butyl, and heptadecyl underwent a
coupling reaction with α-methyl substituted secondary allyl
alcohol 2a successfully generating corresponding coupling
products in good yields (3a−3d). Gratifyingly, it was found
that acrylates containing bulky and chiral substituents such as
menthol and borneol derivative did not effect the reaction in
terms of yield and reactivity, affording corresponding products
(3e and 3f) in 77% and 80% yield, respectively. It is
noteworthy to mention that phenyl acrylate can provide side
products due to competitive reactive sites, but generated
product 3g without having any impact on yield (75%).
Interestingly, the versatility of this methodology was not
restricted only to the acrylates, since activated olefins such as
ethyl vinyl ketone and phenyl vinyl sulfone were found to be
equally effective for C−H functionalization with allyl alcohol
2a and corresponding C−C coupling reaction was observed in
each case with moderate yield (3i, 60% and 3j, 55%) and
excellent stereoselectivity. We further extended the scope of
the reaction by choosing β-substituted allyl alcohol 2b as a
coupling source, since it was a primary alcohol. The
corresponding aldehyde product was observed after reacting
with various acrylates (3k−3u). The trans stereochemistry of
the double bond was further confirmed by comparison with
literature reported data of 3u2.41 It is surprising that, when we
used allyl alcohol 2c as a coupling partner with methyl acrylate
1b, coupled product 3v was observed with double bond
migration toward the ester side (instead of toward aldehyde)
which was confirmed by NMR analysis with the reported
data.42,43 It is necessary to highlight that, to date, there is no
report of synthesis of crucial intermediate 3v in a single step
obtained under catalytic conditions. The traditional reported
synthesis requires a five-step longest linear sequence to prepare
3v using a protection−deprotection strategy.44,45 To further
evaluate the efficiency and potential of this coupling reaction, a
scale-up experiment was performed. Gram-scale synthesis of 3v
by the reaction of allyl alcohol 2c (1.17g) with methyl acrylate
(1.5 g) 1b gave identical results in terms of yield (1.47g, 60%)
and stereoselectivity, indicating the robustness and practicality
of this method. To check the reproducibility of this product,
we carried out the coupling reaction with various acrylates such
as butyl, cyclohexyl, menthol, and borneol which successfully
generated similar products (3w−3z) with moderate to good
yields, highlighting the broad scope of both coupling partners.
It was delightful and interesting to observe that secondary
allyl alcohols (2d−2k) without having any β-substitution
smoothly underwent reaction to afford coupling products (4a−
4j). Various substituents and functional groups on the alkyl
chain of the secondary allyl alcohol such as phenyl, bromo,
benzyl, acetate, and CO2Me were well tolerated (Table 3).
The past decade has witnessed a significant enhancement in
academic and industrial interest for pungent Zanthoxylum-
derived alkylamides, due to the universal interest for both
culinary and medicinal applications. Sanshools are the main
alkylamide natural products found in the pericarp of the fruit,
Szechuan pepper (Zanthoxylum piperitum).46 It is observed
that the olefin geometry of these natural products can
dramatically alter both the degree and specific nature of the
observed biological activities; thus, it is important to have
diastereomerically pure compounds for all biological studies.
Table 3. Scope of Allyl Alcohols
a
Reaction conditions: 1b (0.2 mmol), 2 (0.22 mmol), [Ru(p-
cymene)Cl2]2 (5 mol %), additive (15 mol %), and oxidant (2 equiv)
at 80 °C in a 1,2-dichloroethane (3.0 mL) for 16 h. Isolated yields are
of product 4/4′.
Herein, we demonstrate the application of our reaction by the
shortest synthesis of two natural products, Hydroxy β-Sanshool
and ZP-Amide I, in a highly diastereoselective manner. Several
synthetic reports have been developed for the synthesis of
pungent polyunsaturated fatty acid amides.46−48 A brief
retrosynthetic analysis revealed that the unsaturated alkylamide
5 could be dissected into commercially available amine 6 and
corresponding acid 7, which could be easily achieved from
methyl ester 8. Intermediate 8 could be obtained by a Wittig
reaction between sorbyl bromide 9 and ester-aldehyde 3v.
Initially, a Wittig salt of sorbyl bromide49 was subjected to base
treatment using n-butyl lithium at −78 °C followed by reaction
with aldehyde 3v which provided unsaturated alkyl ester 8 in
68% yield with an approximate 3:1 E/Z stereoselectivity. Ester
8 was then converted into corresponding acid 7 in 70% yield
using LiOH. Finally, coupling of 7 with commercially available
hydroxy amine 6 using HBTU and Et3N afforded hydroxy-β-
sanshool 5 in 65% yield with a 31% overall yield, making it
efficient and the shortest synthesis to date (Scheme 3).47,48
Also demonstrated was the first total synthesis of the other
natural product called ZP-amide I48 10, a isobutylhydrox-
yamide isolated from Sichuan peppers. Aldehyde 3v was
subjected to Takai olefination50 using CrCl2 and iodoform,
providing corresponding vinyl iodide derivative 11 with 65%
Scheme 3. Total Synthesis of Hydroxy β-Sanshool and ZP-
amide I
C
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yield. Compound 11 could be utilized for many coupling
reactions and other functional group transformations, since it
appears as a part the natural product like Lactimidomycin.51,52
LiOH mediated hydrolysis followed by coupling with hydroxy
amine 6 using HBTU and Et3N afforded corresponding amide
12 in 60% yield. Amide 12, on Heck reaction53 with methyl
acrylate 1b using palladium acetate, generated ester-amide 13
in 70% yield. Finally, hydrolysis of the ester group of 13 using
LiOH provided natural product ZP-amide I 10 in 75% yield
with a 21% overall yield (Scheme 3). The synthetic utility of
our method was further demonstrated by synthesizing the key
penultimate precursor for antitumor Chondrillin 14a and
Plakorin 14b in one step (Scheme 4).54 Ru-catalyzed coupling
Scheme 5. Mechanistic Studies
which confirms that the other regioisomer formation was due
to alkene isomerism.
Based on the above result and literature support, a plausible
reaction mechanism for the ruthenium-catalyzed coupling
reaction is depicted in Scheme 6.39,40,57 The catalytic cycle is
Scheme 4. Formal Synthesis of Chondrillin and (+)-cis-
Solamin A
Scheme 6. Plausible Reaction Mechanism
of secondary allyl alcohol 15 and methyl acrylate 1b provided
enone-ester intermediate 16a and 16b, respectively, in 66%
and 63% yield with excellent regioselectivity. (Snider et al.
reported the synthesis of 16a/b in six steps starting from
phenol by MOM protection, n-BuLi mediated alkylation,
deprotection, and then Wessely oxidation using lead
tetraaceate followed by photolysis in methanol and base
hydrolysis.)54 Snider et al. reported that intermediates 16a and
16b were converted to Chondrillin 14a and Plakorin 14b
under photochemical condition using rose bengal and
oxygen.54 So, this constitutes the shortest synthesis of
Chondrillin and Plakorin. Next, the efficacy of this method
for the synthesis of fascinating natural product, (+)-cis-solamin
A 17 (known for cytotoxicity and hemolytic properties), is
depicted in Scheme 4.55,56 We have achieved the synthesis of
crucial intermediate 18 in two steps via Wittig reaction using
aldehyde 3v and tridecyl bromide 19 in 70% yield.
Regioselective asymmetric dihydroxylation of 18 using AD-
mix-α provided diol 20 with 88% ee in 70% yield. Diol 20 is
converted to cis-Solamin A in seven steps by Donohoe et al.55
To understand the mechanistic pathway of the current
coupling reaction, we carried out a deuterium experiment
(Scheme 5). Deuterated allyl alcohol 2e′ on treatment with
methyl acrylate 1b under standard reaction conditions
generated the coupling compound which has no deuterium,
initiated by hydroxy group coordination to in situ generated
reactive cationic ruthenium complex RuX2L (A), followed by
β-hydride elimination which would produce a ruthenium
hydride species (C). In the presence of activated olefins, the
intermediate (C) could undergo reductive elimination
followed by oxidative addition of both the olefins leading to
the formation of a five-membered ruthenacycle (E). β-Hydride
elimination followed by reductive elimination would generate
the product (G) along with a Ru(0) species. The resulting
[Ru(0)] (H) may be reoxidized in the presence of Cu(OAc)2,
to regenerate the ruthenium(II) cationic reactive complex A
for the next catalytic cycle.
In summary, we have developed a novel C−C bond forming
reaction by ruthenium-catalyzed hydroxy directed sp2 C−H
activation of allyl alcohols followed by oxidative coupling with
activated olefins. The developed reaction requires mild
reaction conditions, shows a broad substrate scope, and
functional group tolerance.
1
and its H NMR was exactly matched with product 4d, which
shows that after isomerization the α-proton of the allyl alcohol
is no longer involved in the catalytic system. Also to check
whether another regioisomer was formed due to either alkene
isomerism or incomplete cross-coupling reactions, we con-
ducted two coupling reactions by utilizing 1:5 and 5:1 molar
ratios of acrylate and allyl alcohol. It was observed that the
cross-coupling product was formed exclusively without
significant change in the regioisomeric ratios in both cases,
D
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00200.
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AUTHOR INFORMATION
Corresponding Author
■
Dattatraya H. Dethe − Department of Chemistry, Indian
Institute of Technology Kanpur, Kanpur 208016, India;
orcid.org/0000-0003-2734-210X; Email: ddethe@
iitk.ac.in
Author
Nagabhushana C B − Department of Chemistry, Indian
Institute of Technology Kanpur, Kanpur 208016, India
Complete contact information is available at:
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(18) Hoffman, T. J.; Rigby, J. H.; Arseniyadis, S.; Cossy, J. Synthesis
of Vinyl-Functionalized Oxazoles by Olefin Cross-Metathesis. J. Org.
Chem. 2008, 73, 2400−2403.
Notes
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Rh(III)-Catalyzed C−H Activation as a Tool for the Selective
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
N.C.B. thanks UGC, New Delhi, for the award of a research
fellowship. Financial support from SERB Project No. EMR/
2017/001455 is gratefully acknowledged.
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C-H Alkynylation of Enamides at Room Temperature. Chem.
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